Results of a prospective clinical trial for VAMP alone without irradiation for pediatric favorable, early-stage Hodgkin lymphoma patients who achieve an early complete response

Reporter: Gita Suneja, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2011

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Presenter: Monika Metzger, MD
Presenter's Affiliation: St. Jude Children's Research Hospital

Background

  • Low-risk Hodgkin lymphoma typically refers to stage I-IIA, non-bulky disease in less than 3 sites, and without extranodal involvement.
  • 10-year event free survival (EFS) and overall survival (OS) are 90-95%.
  • Treatment paradigms have evolved over time with a trend toward reducing the toxicity of treatment.
  • Concerning late effects of treatment include:
    • Musculoskeletal: height reduction due to radiation damage to skeletal apparatus
    • Cardiovascular: anthracyclines and mediastinal radiation therapy (RT)
    • Pulmonary: pneumonitis from radiation, bleomycin-mediated toxicity
    • Thyroid: hypothyroidism from RT
    • Gonads: infertility, endocrinopathy, and premature ovarian failure
    • Second malignancies: most commonly breast, thyroid, and non-melanomatous skin cancers
  • In the 1960s, treatment consisted of high-dose radiation therapy (RT) alone to 40 Gy. 5-year disease free survival (DFS) was 60-80% in children with early-stage disease.
  • In the 1970s, concerns about radiation-related late effects led investigators to add the MOPP chemotherapy regimen in order to lower the RT dose to 15-25 Gy. 10-year OS and EFS with these regimens approached 90%.
  • Due to concerns of sterility and second malignancy, ABVD was presented as an alternative chemotherapy regimen. As a result of the findings of CCG 521 demonstrating equivalence of ABVD and MOPP, MOPP was eliminated from first line therapy,
  • Further trials attempted to further limit or completely eliminate radiation therapy from the treatment regimen. Data from the POG 8725, CCG 5942, and GPOH-HD 95 trials demonstrate that low-dose RT may be omitted in certain low-risk patients who respond favorably to chemotherapy without resulting in adverse outcomes; however, excess chemotherapy is required to compensate for the lack of RT, and the patient subgroups for whom RT may be safely omitted are not well-defined.
  • The objective of this study was to evaluate the efficacy of 4 cycles of vinblastine, adriamycin, methotrexate, and prednisone (VAMP) alone in patients with early-stage, favorable Hodgkin lymphoma (HL) who achieve a complete response (CR) after 2 cycles of VAMP.

Methods

  • Multi-institutional phase II trial
  • Included 88 patients with Stage I and II favorable risk HL
  • Favorable risk was defined as no B symptoms, mediastinal bulk, or extranodal disease.
  • Study design:
    • Patients were given VAMP x 2 cycles à evaluation of response
    • If CR à 2 more cycles of VAMP alone
    • If < CR, they received involved field radiation therapy (IFRT) to 25 Gy à then 2 more cycles of VAMP
  • Median age was 14 years
  • Nodular sclerosing was the most common histology, followed by lymphocyte predominant.
  • 44% of patients were stage IA and 56% were IIA
  • Median follow-up was 5.6 years

Results

  • 46 patients achieved a CR, and therefore did not receive radiation therapy. The majority of these patients had lymphocyte predominant histology.
  • 42 patients had < CR, and went on to receive 25 Gy to involved areas. The majority of these patients had nodular sclerosing histology.
  • At 5 years, event-free survival (EFS) was 88% and overall survival (OS) was 100%.
  • There was no difference in EFS between the RT and no RT cohorts
  • In the CR group, there were 5 patients (11%) who experienced treatment failures. Patients were salvaged with multi-agent chemotherapy and IFRT instead of autologous stem cell transplant.
  • In the < CR group, there were 6 (14%) treatment failures. Four of these patients needed autologous stem cell transplant as part of the salvage regimen.
  • Toxicity:
    • Neutropenia was observed in 53/88 pts (60%), but G-CSF use was not required.
    • Febrile neutropenia occurred in 2% of patients or 0.6% of cycles
    • No deaths occurred from infection or other toxicity
    • Treatment delays were rare
  • No second malignancies were observed

Author's Conclusions

  • Risk-adapted, combined-modality therapy using only four cycles of VAMP chemotherapy without radiation for patients with favorable disease and achieving a complete response after 2 cycles of VAMP is highly effective and without significant side effects.
  • Interestingly, based on the results of this study, patients with favorable features can be cured without alkylating agents such as bleomycin and etoposide, or radiation therapy.
  • Non-irradiated patients that relapse can be salvaged with standard chemotherapy without high dose chemotherapy and autologous stem cell transplant.

Implications

  • The importance of late toxicity cannot be underestimated, particularly in patients with low-risk disease.
  • This study suggests that early stage, favorable risk patients with a response to chemotherapy do not need radiation therapy, and that their outcomes are similar to the cohort with lack of complete response receiving radiation therapy.
  • Interesting, patients with < CR were more likely to have nodular sclerosing histology. The authors did not present other features that predicted for < CR vs CR, although this data would be interesting.
  • The subset of patients for whom radiation can be omitted is not fully characterized. While this study helps to establish prognostic factors predicting for < CR or CR, further analysis needs to be performed to help define the subset of patients for whom radiation can safely be omitted.
  • Further information regarding the measurement of response would be very helpful in terms of translating the data presented to clinical practice. For example, were patients evaluated with PET scan in addition to CT scan? What measures were used to gauge CR vs < CR?
  • Finally, the omission of alkylating agents may greatly reduce long-term toxicity from treatment. Further evaluation with longer follow-up is necessary to determine if tumor control will be acceptable with the chemotherapy regimen utilized as part of this study.

English
News
Limited Radiation Acceptable in Pediatric Hodgkin's Lymphoma

Jun 27, 2012 - For patients with favorable-risk Hodgkin's lymphoma who achieve a complete early response to chemotherapy with vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone, two-year event-free survival rates are high with limited use of radiotherapy, according to a study published in the June 27 issue of the Journal of the American Medical Association.



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